Method of making a vascular closure device

ABSTRACT

A method of making a biocompatible, implantable medical device, including a vascular closure device is disclosed. The method includes forming a biocompatible polymer into at least one fiber and randomly orienting the at least one fiber into a fibrous structure having at least one interstitial spaces. Polymeric materials may be utilized to fabricate any of these devices. The polymeric materials may include additives such as drugs or other bioactive agents as well as antibacterial agents. In such instances, at least one agent, in therapeutic dosage, is incorporated into at least one of the fibrous structure and the at least one fiber.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application Ser.No. 60/984,282, filed Oct. 31, 2007 under applicable sections of 35 USC§119.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to vascular closure devices, and moreparticularly to vascular closure devices formed from bioabsorbablepolymers and structures, blends of bioabsorbable polymers andplasticizers, blends of polymers, plasticizers, antibacterial agents andtherapeutic agents, or any combination thereof. These polymeric closuredevices may be prepared by different processes.

2. Discussion of the Related Art

Each year, patients undergo a vast number of surgical procedures in theUnited States. Current data shows about twenty-seven million proceduresare performed per year. Post operative or surgical site infections(“SSIs”) occur in approximately two to three percent of all cases. Thisamounts to more than 675,000 SSIs each year.

The occurrence of SSIs is often associated with bacteria that cancolonize on implantable medical devices used in surgery. During asurgical procedure, bacteria from the surrounding atmosphere may enterthe surgical site and attach to the medical device. Specifically,bacteria can spread by using the implanted medical device as a pathwayto surrounding tissue. Such bacterial colonization on the medical devicemay lead to infection and trauma to the patient. Accordingly, SSIs maysignificantly increase the cost of treatment to patients.

From a clinical perspective, it is generally necessary to administer achemical compound that will provide anti-biotic or anti-bacterial,anti-fungal, or anti-parasitical activity when a vascular closure deviceis used in high-risk patients (e.g., prior MI, stroke, diabetes, oradditional risk factors). Most infections associated with medical deviceare caused by bacteria. The primary mode of infection associated withmedical device is attachment of microorganisms to the device followed bygrowth and formation of a biofilm on the device. Once a biofilm isformed, it is practically impossible to treat the infection withoutactually removing the device.

Implantable medical devices that contain antimicrobial agents applied toor incorporated within have been disclosed and/or exemplified in theart. Examples of such devices are disclosed in European PatentApplication No. EP 0761243. Actual devices exemplified in theapplication include French Percuflex catheters. The catheters weredip-coated in a coating bath containing2,4,4′-tricloro-2-hydroxydiphenyl ether [Ciba Geigy Irgasan; (DP300)]and other additives. The catheters were then sterilized with ethyleneoxide and stored for thirty days. Catheters coated with such solutionsexhibited antimicrobial properties, i.e., they produced a zone ofinhibition when placed in a growth medium and challenged withmicroorganism, for thirty days after being coated.

There have been efforts to prepare antibacterial surgical devices suchas sutures as disclosed in U.S. Pat. No. 6,514,517 B2 (AntibacterialCoatings for Medical Devices); U.S. Pat. No. 6,881,766 B2 (Sutures andCoatings Made from Therapeutic Absorbable Glass) and WO 2004/032704 A2(Packaged Antimicrobial Medical Device and Method of Preparing Same).

There have been several closure devices disclosed in prior art asdescribed in U.S. Pat. No. 6,090,130 (Hemostatic puncture closure systemincluding blood vessel locator and method of use) and U.S. Pat. No.6,179,863 B1 (Hemostatic puncture closure system and method of use) byKensey Nash Corporation; US 2007/0073345 A1 (Vascular sealing devicewith high surface area sealing plug), US 2007/0032824 A1 (Tissuepuncture closure device with track plug), US 2007/0032823 A1 (Tissuepuncture closure device with coiled automatic tamping system), US2006/0265007 A1 (Tissue puncture closure system with retractablesheath), US 2006/0058844 A1 (Vascular sealing device with lockingsystem) and US 2005/0267521 A1 (Collagen sponge for arterial sealing) bySt. Jude Medical; and U.S. Pat. No. 6,969,397 (Guide wire element forpositioning vascular closure devices and method for use) and US2005/0267528 A1 (Vascular plug having composite construction) by EnsureMedical. In these disclosures, bioabsorbable plugs were used forpuncture closure.

Most implantable medical devices are manufactured, sterilized andcontained in packages until opened for use in a surgical procedure.During surgery, the opened package containing the medical device,packaging components contained therein, and the medical device, isexposed to the operating room atmosphere, where bacteria from the airmay be introduced. Incorporating antimicrobial properties into theclosure plug delivery system, package and/or the packaging componentscontained therein substantially prevents bacterial colonization on thepackage and components once the package has been opened. Theantimicrobial package and/or packaging components in combination withthe incorporation of antimicrobial properties onto or into the medicaldevice itself would substantially ensure an antimicrobial environmentabout the sterilized medical device.

SUMMARY OF THE INVENTION

The present invention relates to bioabsorbable vascular closure medicaldevices that may include therapeutic agent(s) and methods for preparingsuch medical devices. In accordance with embodiments of the presentinvention, an agent is disposed on the surfaces, in interstitial spaces,and/or in the bulk of the medical device.

In one embodiment of the invention, the method of making the vascularclosure device includes forming a biocompatible polymer into at leastone fiber and randomly orienting the at least one fiber into a fibrousstructure. The fibrous structure has at least one interstitial spacebetween the at least one randomly oriented fiber. At least one agent, intherapeutic dosage, is incorporated into at least one of the fibrousstructure and the at least one fiber, the agent being configured forcontrolled elution therefrom.

An embodiment of the vascular closure medical device includes anantimicrobial agent disposed thereon, the antimicrobial agent beingselected from halogenated hydroxyl ethers, acyloxydiphenyl ethers, andcombinations thereof, silver containing compounds, chlorhexidinegluconate, methylisothiazolone, terpineol, thymol, chloroxylenol,cetylpyridinium chloride, iodine compounds, chlorinated phenols,quaternary ammonium compounds, biguanide compounds, and gentian violetcompounds. The amount is sufficient to substantially inhibit bacterialcolonization on the medical device.

The present invention is also directed to applying and utilizingvascular closure devices to minimize the potential for infection at thepuncture site.

In accordance with one aspect, the present invention is directed to animplantable medical device which comprises a structure formed from atleast one polymer, and at least one therapeutic agent or antimicrobialagent dispersed throughout the at least one polymer.

In accordance with another aspect, the present invention is directed toan implantable medical device which comprises a structure formed from afirst material, and a coating layer affixed to the first material, thecoating layer including at least one therapeutic agent or antimicrobialagent dispersed throughout a polymeric material.

In accordance with another aspect, the present invention is directed toan implantable medical device which comprises a fibrous structure formedfrom at least one polymer, and at least one therapeutic agent orantimicrobial agent dispersed throughout the at least one polymer.

In accordance with another aspect, the present invention is directed toan implantable medical device which comprises a porous vascular closuredevice formed from at least one polymer, and at least one therapeuticagent or antimicrobial agent dispersed throughout the at least onepolymer.

The implantable medical devices of the present invention may be formedout of any number of biocompatible polymeric materials. In order toachieve the desired properties, the polymeric material, whether in theraw state or in the tubular or sheet or fibrous or porous state may bephysically deformed to achieve a certain degree of alignment of thepolymer chains.

The medical devices of the present invention may also be formed fromblends of polymeric materials, blends of polymeric materials andplasticizers, blends of polymeric materials and therapeutic agents,blends of polymeric materials and antimicrobial agents, blends ofpolymeric materials with both therapeutic and antimicrobial agents,blends of polymeric materials with plasticizers and therapeutic agents,blends of polymeric materials with plasticizers and antimicrobialagents, blends of polymeric materials with plasticizers, therapeuticagents and antimicrobial agents, and/or any combination thereof. Byblending materials with different properties, a resultant material mayhave the beneficial characteristics of each independent material. Inaddition, by blending either or both therapeutic agents andantimicrobial agents together with the other materials, higherconcentrations of these materials may be achieved as well as a morehomogeneous dispersion. Various methods for producing these blendsinclude solvent and melt processes and coating techniques.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing and other features and advantages of the invention will beapparent from the following, more particular description of preferredembodiments of the invention, as illustrated in the accompanyingdrawings.

FIG. 1 is an isometric view of a fibrous antimicrobial plug according toone embodiment of the present invention.

FIG. 2A is a schematic representation of a fiber in the vascular closureplug showing the dispersion of the antimicrobial agent within theindividual fiber structure according to one embodiment of the presentinvention.

FIG. 2B is a schematic representation of a fiber in the vascular closureplug showing the dispersion of the antimicrobial agent within the outerpolymer layer of the fiber structure according to one embodiment of thepresent invention.

FIG. 3 is a schematic representation of the fiber in the vascularclosure plug having a thin coating of spin finish/lubricant plus agentalong the outer surface of the fiber structure according to oneembodiment of the present invention.

FIG. 4A is a schematic representation of a non-woven fibrous mataccording to one embodiment of the present invention.

FIG. 4B is a section view of the non-woven mat depicted in FIG. 4A takenalong reference line A-A.

FIG. 4C is a schematic representation of a non-woven fibrous mataccording to one embodiment of the present invention.

FIG. 4D is a schematic representation of a fibrous antimicrobial plughaving agent dispersed between the fiber structure according to oneembodiment of the present invention.

FIG. 4E is a close-up schematic representation of a portion of a fibrousantimicrobial plug having agent dispersed between the fiber structureaccording to one embodiment of the present invention.

FIG. 5A is a schematic representation of the fiber in the vascularclosure plug having a thin coating of agent along the outer surface ofthe fiber structure according to one embodiment of the presentinvention.

FIG. 5B is a schematic representation of the fiber in the vascularclosure plug having a thin coating of agent along a portion of the outersurface of the fiber structure according to one embodiment of thepresent invention.

FIG. 6A illustrates a plug that has been dip coated with apolymer/agent/solvent solution according to one embodiment of thepresent invention.

FIG. 6B illustrates a plug having agent occupying the interstitialspaces that has been dip coated with a polymer/agent/solvent solutionaccording to one embodiment of the present invention.

FIG. 6C illustrates a plug that has been dip coated with a agent/solventsolution according to one embodiment of the present invention.

FIG. 6D illustrates a plug having agent occupying the interstitialspaces that has been dip coated with a agent/solvent solution accordingto one embodiment of the present invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Implantable medical devices may be fabricated from any number ofsuitable biocompatible materials, including polymeric materials. Theinternal structure of these polymeric materials may be altered utilizingmechanical and/or chemical manipulation of the polymers. These internalstructure modifications may be utilized to create devices havingspecific gross characteristics such as crystalline and amorphousmorphology and orientation as is explained in detail subsequently.Although the present invention applies to any number of implantablemedical devices, for ease of explanation, the following detaileddescription will focus on an exemplary vascular closure device.

In accordance with the present invention, implantable medical devicesmay be fabricated from any number of biocompatible materials, includingpolymeric materials. These polymeric materials may be non-degradable,biodegradable and/or bioabsorbable. These polymeric materials may beformed from single polymers, blends of polymers and blends of polymersand plasticizers. In addition, other agents such as drugs and/orantimicrobial agents may be blended with the materials described aboveor affixed or otherwise added thereto. A number of chemical and/orphysical processes may be utilized to alter the chemical and physicalproperties of the materials and ultimately the final devices.

Exemplary Devices

Catheterization and interventional procedures, such as angioplasty andstenting, generally are performed by inserting a hollow needle through apatient's skin and muscle tissue into the vascular system. This createsa puncture wound in a blood vessel, frequently the femoral artery,which, once the interventional procedure has been completed, needs to beclosed or sealed in a suitable manner.

Procedures and devices have been proposed for accomplishing such closurewhich involve the use of an introducer sheath that is placed in thetract of the puncture wound following which a closure delivering deviceis introduced through the introducer sheath to deploy a sealing orclosing element within the tract. The vascular closure device in oneembodiment of the present invention is one such device. The vascularclosure device substantially occludes blood flow from a puncture.

In a preferred embodiment, the vascular closure device is a porous plugpreferably prepared from a bioabsorbable material. There are severalapproaches that can be used to make these plugs with antibacterialadditives.

It is generally known to use multilayered fabrics in connection withmedical procedures. For example, multilayered fabrics are used as allpurpose pads, wound dressings, surgical meshes, including hernia repairmeshes, adhesion prevention meshes and tissue reinforcement meshes,defect closure devices, and hemostats. Additionally, multilayeredfabrics are useful for tissue engineering and orthopedic applications.The recent emergence of tissue engineering offers numerous approaches torepair and regenerate damaged/diseased tissue. Tissue engineeringstrategies have explored the use of biomaterials that ultimately canrestore or improve tissue function. The use of colonizable andremodelable scaffolding materials has been studied extensively as tissuetemplates, conduits, barriers and reservoirs. In particular, syntheticand natural materials in the form of foams, sponges, gels, hydrogels,textiles, and nonwovens have been used in vitro and in vivo toreconstruct/regenerate biological tissue, as well as deliver agents forinducing tissue growth. The different forms of scaffolds may belaminated to form a multilayered tissue engineering scaffold.

As used herein, the term “nonwoven fabric” includes, but is not limitedto, bonded fabrics, formed fabrics, or engineered fabrics, that aremanufactured by processes other than spinning, weaving or knitting. Morespecifically, the term “nonwoven fabric” refers to a porous,textile-like material, usually in flat sheet form, composed primarily orentirely of staple fibers assembled in a web, sheet or bats. Thestructure of the nonwoven fabric is based on the arrangement of, forexample, staple fibers that are typically arranged more or lessrandomly. The tensile stress-strain and tactile properties of thenonwoven fabric ordinarily stem from fiber to fiber friction created byentanglement and reinforcement of, for example, staple fibers, and/orfrom adhesive, chemical or physical bonding. Notwithstanding, the rawmaterials used to manufacture the nonwoven fabric may be yarns, scrims,netting, or filaments made by processes that include spinning, weavingor knitting.

Preferably, the nonwoven fabric is made by processes other thanspinning, weaving or knitting. For example, the nonwoven fabric may beprepared from yarn, scrims, netting or filaments that have been made byprocesses that include spinning, weaving or knitting. The yarn, scrims,netting and/or filaments are crimped to enhance entanglement with eachother and attachment to the second absorbable woven or knitted fabric.Such crimped yarn, scrims, netting and/or filaments may then be cut intostaple that is long enough to entangle. The staple may be between about0.1 and 3.0 inches long, preferably between about 0.75 and 2.5 inches,and most preferably between about 1.5 and 2.0 inches. The staple may becarded to create a nonwoven bat, which may be then needle-punched orcalendared into an absorbable nonwoven fabric. Additionally, the staplemay be kinked or piled.

FIG. 4A is a schematic representation of a non-woven fibrous mataccording to one embodiment of the present invention. The non-woven mat105 is formed from filaments or fibers 101 entangled in random order. Ina preferred embodiment, the non-woven mat 105 also includes anantibacterial or antimicrobial agent 102 dispersed throughout the mat,either in, on or between the entangled fibrous structure.

Other methods known for the production of nonwoven fabrics may beutilized and include such processes as air laying, wet forming andstitch bonding. Such procedures are generally discussed in theEncyclopedia of Polymer Science and Engineering, Vol. 10, pp. 204-253(1987) and Introduction to Nonwovens by Albin Turbak (Tappi Press,Atlanta Ga. 1999), both incorporated herein in their entirety byreference.

The thickness of the nonwoven fabric may range from about 0.25 to 2 mm.The basis weight of the nonwoven fabric ranges from about 0.01 to 0.2g/in²; preferably from about 0.03 to 0.1 g/in²; and most preferably fromabout 0.04 to 0.08 g/in².

Additionally, the nonwoven fabric may comprise pharmacologically andbiologically active agents, including but not limited to, wound healingagents, antibacterial agents, antimicrobial agents, growth factors,analgesic and anesthetic agents. When used as a tissue scaffold, thereinforced absorbable multilayer fabric may be seeded or cultured withappropriate cell types prior to implantation for the targeted tissue.

A typical process to make the vascular closure plug according to oneembodiment of the present invention is as follows:

The desired absorbable polymer resin [e.g., poly (glycolic acid)] ismelt extruded in to multi-filaments (about 40 to 70 filaments) withdifferent denier (about 120 to 150 denier) and tenacity (about 3 to 7grams/denier). During the melt spinning process, a spin finish isapplied on the fiber surface to prevent excessive fiber breakage. Thefibers are then crimped and cut in to short staple fibers (for example,1-2 inches staple lengths), carded and needle punched to prepare anon-woven mat with the desired density and integrity. The mat is rinsed(scoured) with a solvent (e.g., isopropanol or acetone or hexane, ethylacetate or other co-solvents) to remove the spin finish and dried; andthen cut in to cylindrical plugs or other desired geometry.

FIG. 1 is an isometric view schematically representing a fibrousantimicrobial plug according to one embodiment of the present invention.The plug 100 includes randomly oriented fiber or fibers 101. In apreferred embodiment the plug 100 may also include an agent, preferablyan antibacterial or antimicrobial agent on, within or in between thefibers 101. In addition the agent may be coated over the entire plug100.

The antibacterial (or any other agents) is added by different ways inthe above-mentioned manufacturing process as described below in furtherdetails.

In one embodiment of the invention, the agent may be added (bulk loaded)in the fiber matrix during the melt spinning process. FIG. 2A shows thedispersion of the antimicrobial agent in the fiber matrix forming theplug 100 according to one embodiment of the present invention. The bulkloaded fiber 101 is comprised of an agent 102 dispersed within a polymer103. One way this is achieved is by preparing a master batch concentrateof the agent 102 and then adding desired amount of the concentrate tothe polymer 103 during the fiber extrusion process. This allows uniformdispersion of large quantity of the agent 102 in the fiber 101 andprovides long-term diffusion of the agent 102 during the life cycle ofthe plug 100 in the vascular environment. The agent 102 is preferablythermally stable at melt processing temperatures. Alternatively, theagent 102 can be added on, or incorporated into a polymeric layer on thefiber 101 surfaces. FIG. 2B is a schematic representation of a fiber inthe plug 100 showing the dispersion of the agent within the outerpolymer layer of the fiber structure according to one embodiment of thepresent invention. This type of fiber 101 may be formed by mixing theagent 102 with a low melting polymer 203 (e.g.,Polycaprolactone/Polyglycolic acid copolymer) to form a sheath on thecore fiber (filament) 103 (e.g., PGA) using a bicomponent fiber spinningtechnology. Referring again to FIG. 2B, the antimicrobial agent 102 isdispersed within polymer layer 203, which is coated on the base polymer103. Together, this bicomponent fiber 101 forms the fibrous structure ofthe plug 100.

In accordance with another embodiment of the invention, the agent 102may be mixed with the spin finish that is coated during the meltspinning process. This approach allows the agent 102 to disperseuniformly on the fiber 101 surfaces. FIG. 3 is a schematicrepresentation of the fiber 101 comprising the plug 100 having a thincoating 104 along the outer surface of the fibrous structure 101. Thescouring process should not be used to remove the surface coatings whenusing this approach. Accordingly, the thin outer coating 104 comprisesthe spin finish/lubricant plus the agent 102.

In another embodiment of the invention, the agent may be dip coated onthe scoured non-woven mat 105, which is then cut into plugs 100. The dipcoating solution 404 comprises the agent 102 and a bioabsorbable polymer(e.g., Polycaprolactone/Polyglycolic acid) and may also include asolvent. One embodiment of the invention illustrating a non-woven matthat has been dip coated with an agent 102 and polymer is illustrated inFIGS. 4A and 4B. As earlier described, FIG. 4A is an isometric schematicrepresentation of a non-woven fibrous mat the non-woven mat 105 made upof randomly oriented fibers 101. For clarity, FIG. 4B is a section viewof the mat 105 depicted in FIG. 4A taken along section line A-A. In eachview the dip coating solution 404 is shown encapsulating the outersurfaces of the mat 105. During the solvent removal process, the agent102 and the polymer are coated uniformly on the fiber 101 surfaces.Alternatively, the agent 102 can be added on the mat 105 surface in theabsence of the bioabsorbable polymer. In this embodiment, the agent 102coating on the non-woven mat 105 may be non-uniform. An isometricschematic representation of a mat 105 having a non-uniform agent 102coating on the mat 105 surface in illustrated in FIG. 4C.

It should be noted that the coating process might also allow the dipcoating solution 404 or agent 102, as the case may be, to penetrate theexterior surface of the mat 105 into the interstitial spaces formedbetween adjacent fibers 101. FIG. 4D is a schematic representation of aplug 101 wherein the agent 102 has penetrated the surface and resides inthe interstitial spaces between fibers 101. FIG. 4E is a close upsection view of entangled fibers 101 forming the interstitial spacesoccupied by agent 102. Although not explicitly depicted, the plug 101may have agent 102 or solution 404 covering the top and bottoms ends ofthe cylindrical plug 101. In addition, the coating process may allowsome amount of agent or coating solution 404 to cover various sidesections of the plug 101.

FIGS. 5A and 5B are schematic representations of another embodiment ofthe invention where the extruded filaments 101 are first scoured toremove the spin finish, and the scoured filaments 101 are dip coatedwith the coating solution 404 (polymer, agent and solvent). During thesolvent removal process, the polymer and agent coating 104 dispersesuniformly on the filaments 101 as shown in FIG. 5A. These filaments arethen crimped, carded, needle punched into a mat 105 and then cut in toplugs 100. Alternatively, the scoured filaments 101 may be dip coated inan agent/solvent solution. During the solvent removal process, the agent102 remains on the filament 101. The agent may uniformly cover thefilament 102, but generally will non-uniformly cover the filament 102 asillustrated in FIG. 5B. These filaments are then crimped, carded, needlepunched into a mat 105 and then cut in to plugs 100.

In still another embodiment of the invention, the plugs 100 preparedfrom the non-woven mat 105 may be covered with a coating after plugformation. This coating may be in the form of a solution or a powder. Byway of example a solution of polymer and agent; polymer, agent andsolvent; or agent and solvent may be applied to the formed plug 100. Inaddition, the coating may be applied to the plug 100 in a powdered form,such as through an electrostatic coating process.

FIGS. 6A-6D are schematic representations illustrating plugs 100 coveredafter formation with a coating. In particular, FIG. 6A illustrates aplug 101 that has been dip coated with a polymer/agent/solvent solution.When the solvent is removed, the polymer and agent substantiallyencapsulates the outer surfaces of the plug 100 with a thin coating 404.In addition, the plug 100 may have been originally prepared with theagent occupying the interstitial spaces formed between adjacent randomlyoriented fibers 101 before coating. FIG. 6B illustrates a plug 101having agent occupying the interstitial spaces that has been dip coatedwith a polymer/agent/solvent solution.

Alternatively, the plug 100 may be dip coated with an agent/solventsolution. When the solvent is removed, the agent 102 may non-uniformlycover the outer surfaces of the plug 100. FIG. 6C is a schematicrepresentation illustrating a plug 100 covered by a non-uniform coatingof agent 102 according to one embodiment of the present invention. Inaddition, the plug 100 may have been originally prepared with the agent102 occupying the interstitial spaces formed between adjacent randomlyoriented fibers 101 before coating. FIG. 6D illustrates a plug 101having agent occupying the interstitial spaces that has been dip coatedwith an agent/solvent solution.

There are several alternative methods that can be used to have the agenteither dispersed within the fiber matrix or on the fiber surface toprovide the antimicrobial properties.

The components of the porous closure device have therapeutic aentsl andpolymer coating combinations that are used to deliver the various agentsand drugs, i.e. therapeutic and/or pharmaceutical agents including:antiproliferative/antimitotic agents including natural products such asvinca alkaloids (i.e. vinblastine, vincristine, and vinorelbine),paclitaxel, epidipodophyllotoxins (i.e. etoposide, teniposide),antibiotics (dactinomycin (actinomycin D) daunorubicin, doxorubicin andidarubicin), anthracyclines, mitoxantrone, bleomycins, plicamycin(mithramycin) and mitomycin, enzymes (L-asparaginase which systemicallymetabolizes L-asparagine and deprives cells which do not have thecapacity to synthesize their own asparagine); antiplatelet agents suchas G(GP)II_(b)III_(a) inhibitors and vitronectin receptor antagonists;antiproliferative/antimitotic alkylating agents such as nitrogenmustards (mechlorethamine, cyclophosphamide and analogs, melphalan,chlorambucil), ethylenimines and methylmelamines (hexamethylmelamine andthiotepa), alkyl sulfonates-busulfan, nirtosoureas (carmustine (BCNU)and analogs, streptozocin), trazenes-dacarbazinine (DTIC);antiproliferative/antimitotic antimetabolites such as folic acid analogs(methotrexate), pyrimidine analogs (fluorouracil, floxuridine, andcytarabine), purine analogs and related inhibitors (mercaptopurine,thioguanine, pentostatin and 2-chlorodeoxyadenosine {cladribine});platinum coordination complexes (cisplatin, carboplatin), procarbazine,hydroxyurea, mitotane, aminoglutethimide; hormones (i.e. estrogen);anticoagulants (heparin, synthetic heparin salts and other inhibitors ofthrombin); fibrinolytic agents (such as tissue plasminogen activator,streptokinase and urokinase), aspirin, dipyridamole, ticlopidine,clopidogrel, abciximab; antimigratory; antisecretory (breveldin);antiinflammatory: such as adrenocortical steroids (cortisol, cortisone,fludrocortisone, prednisone, prednisolone, 6α-methylprednisolone,triamcinolone, betamethasone, and dexamethasone), non-steroidal agents(salicylic acid derivatives i.e. aspirin; para-aminophenol derivativesi.e. acetominophen; indole and indene acetic acids (indomethacin,sulindac, and etodalac), heteroaryl acetic acids (tolmetin, diclofenac,and ketorolac), arylpropionic acids (ibuprofen and derivatives),anthranilic acids (mefenamic acid, and meclofenamic acid), enolic acids(piroxicam, tenoxicam, phenylbutazone, and oxyphenthatrazone),nabumetone, gold compounds (auranofin, aurothioglucose, gold sodiumthiomalate); immunosuppressives: (cyclosporine, tacrolimus (FK-506),sirolimus (rapamycin), azathioprine, mycophenolate mofetil); angiogenicagents: vascular endothelial growth factor (VEGF), fibroblast growthfactor (FGF) platelet derived growth factor (PDGF), erythropoetin;angiotensin receptor blocker; nitric oxide donors; anti-senseoligionucleotides and combinations thereof; cell cycle inhibitors, mTORinhibitors, and growth factor signal transduction kinase inhibitors.

The closure device can be made from biodegradable or bioabsorbablepolymer compositions. The type of polymers used can degrade viadifferent mechanisms such as bulk or surface erosion. Bulk erodiblepolymers include aliphatic polyesters such poly (lactic acid); poly(glycolic acid); poly (caprolactone); poly (p-dioxanone) and poly(trimethylene carbonate); and their copolymers and blends. Otherpolymers can include amino acid derived polymers; phosphorous containingpolymers [e.g., poly (phosphoesters)] and poly (ester amide). Surfaceerodible polymers include polyanhydrides and polyorthoesters. Theclosure device can be made from combinations of bulk and surfaceerodible polymers to control the degradation mechanism of the stent. Theselection of the polymers will determine the absorption of that can bevery short (few weeks) and long (weeks to months).

The bioabsorbable compositions to prepare the closure device will alsoinclude drug and other agents such as antibacterial materials. The drugor agent will release by diffusion and during degradation of the closuredevice. The porous structure to prepare vascular closure device can befabricated either by melt or solvent processing.

The medical devices described herein are generally implantable medicaldevices, including but not limited to mono and multifilament sutures,surgical meshes such as hernia repair mesh, hernia plugs, brachy seedspacers, suture clips, suture anchors, adhesion prevention meshes andfilms, and suture knot clips. Also included are implantable medicaldevices that are absorbable and non-absorbable. An absorbable polymer isdefined as a polymer that, when exposed to physiological conditions,will degrade and be absorbed by the body over a period of time.Absorbable medical devices typically are formed from generally known,conventional absorbable polymers including, but not limited to,glycolide, lactide, co-polymers of glycolide, or mixtures of polymers,such as polydioxanone, polycaprolactone and equivalents thereof.Examples of absorbable medical device include mono and multifilamentsutures. The multifilament suture includes sutures wherein a pluralityof filaments is formed into a braided structure. Examples ofnon-absorbable medical devices include mono and multifilament sutures,surgical meshes such as hernia repair mesh, hernia plugs and brachy seedspacers, which may be polymeric or nonpolymeric.

Suitable antimicrobial agents may be selected from, but are not limitedto, halogenated 5 hydroxyl ethers, acyloxydiphenyl ethers, orcombinations thereof. In particular, the antimicrobial agent may be ahalogenated 2-hydroxy diphenyl ether and/or a halogenated 2-acyloxydiphenyl ether, as described in U.S. Pat. No. 3,629,477.

Antimicrobial activity similar to that of the halogen-o-hydroxy-diphenylethers is also attained using the O-acyl derivatives thereof whichpartially or completely hydrolyze under the conditions for use inpractice. The esters of acetic acid, chloroacetic acid, methyl ordimethyl carbamic acid, benzoic acid, chlorobenzoic acid, methylsulfonicacid and chloromethylsulfonic acid are particularly suitable.

One particularly preferred antimicrobial agent within the scope of theabove formula is 2,4,4′-trichloro-2′-hydroxydiphenyl ether, commonlyreferred to as triclosan (manufactured by Ciba Geigy under the tradename Irgasan DP300 or Irgacare MP). Triclosan is a broad-spectrumantimicrobial agent that has been used in a variety of products, and iseffective against a number of organisms commonly associated with SSIs.Such microorganisms include, but are not limited to, genusStaphylococcus, Staphylococcus epidermidis, Staphylococcus aureus,methicillin-resistant Staphylococcus epidermidis, methicillin-resistantStaphylococcus aureus, and combinations thereof.

It is advantageous to use a coating composition as a vehicle fordelivering the antimicrobial agent to the surface of the device wheresuch coating already is used conventionally in the manufacture of thedevice, such as, for example, absorbable and nonabsorbable vascularclosure plug. Examples of medical devices, as well as coatings that maybe applied thereto, may be found in U.S. Pat. Nos. 4,201,216, 4,027,676,4,105,034, 4,126,221, 4,185,637, 3,839,297, 6,260,699, 5,230,424,5,555,976, 5,868,244, 5,972,008 and WO 2004/032704 A2, each of which ishereby incorporated herein in its entirety. As disclosed in U.S. Pat.No. 4,201,216, the coating composition may include a film-formingpolymer and a substantially water-insoluble salt of a C6 or higher fattyacid. As another example, an absorbable coating composition that may beused for an absorbable medical device may include poly(alkyleneoxylates) wherein the alkylene moieties are derived from C6 or mixturesof C4 to C12 diols, which is applied to a medical device from a solventsolution, as disclosed in U.S. Pat. No. 4,105,034. The coatingcompositions of the present invention may include a polymer orco-polymer, which may include lactide and glycolide, as a binding agent.The compositions may also include calcium stearate, as a lubricant, andan antimicrobial agent. Medical devices not conventionally employing acoating in the manufacturing process, however, also may be coated with acomposition comprising an antimicrobial agent. The coating may beapplied to the device by, for example, dip coating, spray coating,suspended drop coating, or any other conventional coating means.

Microorganisms of the genus Staphylococcus are the most prevalent of allof the organisms associated with device-related surgical site infection.S. aureus and S. epidermidis are commonly present on patients' skin andas such are introduced easily into wounds. One of the most efficaciousantimicrobial agents against Staphylococcus is2,4,4′-trichloro-2′hydroxydiphenyl ether. This compound has a minimuminhibitory concentration (MIC) against S. aureus of 0.01 ppm, asmeasured in a suitable growth medium and as described by Bhargava, H. etal in the American Journal of Infection Control, June 1996, pages209-218. The MIC for a particular antimicrobial agent and a particularmicroorganism is defined as the minimum concentration of thatantimicrobial agent that must be present in an otherwise suitable growthmedium for that microorganism, in order to render the growth mediumunsuitable for that microorganism, i.e., the minimum concentration toinhibit growth of that microorganism. The phrase “an amount sufficientto substantially inhibit bacterial colonization” as used herein isdefined as the minimum inhibitory concentration for S. aureus orgreater.

A demonstration of this MIC is seen in the disk diffusion method ofsusceptibility. A filter paper disk, or other object, impregnated with aparticular antimicrobial agent is applied to an agar medium that isinoculated with the test organism. Where the anti-microbial agentdiffuses through the medium, and as long as the concentration of theantimicrobial agent is above the minimum inhibitory concentration (MIC),none of the susceptible organism will grow on or around the disk forsome distance. This distance is called a zone of inhibition. Assumingthe antimicrobial agent has a diffusion rate in the medium, the presenceof a zone of inhibition around a disk impregnated with an antimicrobialagent indicates that the organism is inhibited by the presence of theantimicrobial agent in the otherwise satisfactory growth medium. Thediameter of the zone of inhibition is inversely proportional to the MIC.

Alternatively, the concentration of triclosan on the surface of amedical device such as a coated vascular closure plug may be greaterthan about 0.01 ppm (wt./wt. coating) or between about 30 ppm to 5,000ppm (wt./wt. plug). The concentration of triclosan on the surface of thedelivery system or package or containment compartment may be betweenabout 5 ppm to 5,000 ppm (wt./wt. package or compartment). For otherparticular applications, however, higher amounts of antimicrobial agentmay be useful and should be considered well within the scope of thepresent invention.

In accordance with various methods of the present invention, a packageand containment compartment that are initially substantially free of anantimicrobial agent, i.e., no antimicrobial agent is intended to bepresent on the package or containment compartment surfaces, may beprovided. A medical device, which has an antimicrobial agent disposedthereon, is positioned within the package or containment compartment.Subsequently, the package, the containment compartment if utilized andthe medical device are subjected to time, temperature and pressureconditions sufficient to vapor transfer a portion of the antimicrobialagent from the medical device to the package and/or the containmentcompartment.

The rate of transfer of an antimicrobial agent such as triclosan fromthe medical device to the package and/or containment compartment issubstantially dependent upon the time, temperature and pressureconditions under which the package with the containment compartment andthe medical device is processed, stored and handled. For example,triclosan is capable of transferring from a vascular plug to acontainment compartment (in a closed vial at atmospheric pressure) whenthe temperature is maintained at 55° C. over a period of time. Theconditions to effectively vapor transfer an antimicrobial agent such astriclosan include a closed environment, atmospheric pressure, atemperature of greater than 40° C., for a period of time ranging from 4to 8 hours. Also included are any combinations of pressure andtemperature to render a partial pressure for the antimicrobial agentthat is the same as the partial pressure rendered under the conditionsdescribed above, in combination with a period of time sufficient torender an effective amount or concentration of the antimicrobial agenton the package and/or containment compartment, i.e., the minimuminhibitory concentration (MIC) or greater. Specifically, it is known toone of ordinary skill that if the pressure is reduced, the temperaturemay be reduced to effect the same partial pressure. Alternatively, ifthe pressure is reduced, and the temperature is held constant, the timerequired to render an effective amount or concentration of theantimicrobial agent on the package and/or containment compartment may beshortened. While a portion of the antimicrobial agent is transferred tothe package and/or containment compartment during this process, a secondportion is retained on the surface of the medical device. Accordingly,after the transfer, the medical device and the package and/or thecontainment compartment contain the antimicrobial agent in an amounteffective to substantially inhibit bacterial colonization thereon andthereabout.

Example 1

Coating experiments were conducted using a PGA plug to evaluate theeffect of triclosan as an antibacterial agent for vascular closuredevices. Each plug was hand dipped in a coating solution for 10 secondsand then air dried at ambient temperature for 2 h. Table I summarizesthe coating compositions. Samples 1 to 6 were packaged in universalfolders containing vapor hole without tyvek patches, and samples 7 and 8were packaged in universal folders containing the vapor hole and dosedtyvek patches. All the samples were sterilized by ethylene oxide. Thesterilized plug samples were then cut into two pieces and tested againsttwo strains of bacteria namely, Staphylococcus aureus and Escherichiacoli, to determine zone of inhibition (ZOI). Table I summarizes theresults from this test. The ZOI results show that all plug samplesprovide anti bacterial effects for S. aureus bacteria exceeding 40 mm;and different levels of inhibition (from 7.7 mm to greater than 40 mm)for E. coli bacteria.

TABLE I Summary of coating compositions and zone of inhibition for PGAplugs Zone of Inhibition (mm) Sample ID Substrate Sample Type CoatingComposition S. aureus E. Coli 1 PGA plug Control No Coating 0 0 2 PGAplug Coated 2% w/w triclosan in ethyl acetate (no polymer) >40 7.7 3 PGAplug Coated 2% w/w triclosan and 5% w/w PLGA 65/35 in ethyl acetate >4014.5 4 PGA plug Coated 2% w/w triclosan and 1% w/w PLGA 65/35 in ethylacetate >40 14.5 5 PGA plug Coated 2% w/w triclosan and 5% w/w PCL/PGA90/10 in ethyl acetate >40 >40 6 PGA plug Coated 2% w/w triclosan and 1%w/w PCL/PGA 90/10 in ethyl acetate >40 >40 7 PGA plug Vapor 8 mgtriclosan in tyvek patch by vapor deposition (no polymer) >40 14.5 8 PGAplug Vapor 4 mg triclosan in tyvek patch by vapor deposition (nopolymer) >40 14.5Material Characteristics

Accordingly, in one exemplary embodiment, a vascular closure device maybe fabricated from a material such as a polymeric material includingnon-crosslinked thermoplastics, cross-linked thermosets, composites andblends thereof. There are typically three different forms in which apolymer may display the mechanical properties associated with solids;namely, as a crystalline structure, as a semi-crystalline structureand/or as an amorphous structure. All polymers are not able to fullycrystallize, as a high degree of molecular regularity within the polymerchains is essential for crystallization to occur. Even in polymers thatdo crystallize, the degree of crystallinity is generally less than onehundred percent. Within the continuum between fully crystalline andamorphous structures, there are two thermal transitions possible;namely, the crystal-liquid transition (i.e. melting point temperature,T_(m)) and the glass-liquid transition (i.e. glass transitiontemperature, T_(g)). In the temperature range between these twotransitions there may be a mixture of orderly arranged crystals andchaotic amorphous polymer domains.

Molecular orientation is important as it primarily influences bulkpolymer properties and therefore will have a strong effect on the finalproperties that are essential for different material applications.Physical and mechanical properties such as permeability, wear,refractive index, absorption, degradation rates, tensile strength, yieldstress, tear strength, modulus and elongation at break are some of theproperties that will be influenced by orientation. Orientation is notalways favorable as it promotes anisotropic behavior. Orientation mayoccur in several directions such as uniaxial, biaxial and multiaxial. Itmay be induced by drawing, rolling, calendaring, spinning, blowing, andany other suitable process, and is present in systems including fibers,films, tubes, bottles, molded and extruded articles, coatings, andcomposites. When a polymeric material is processed, there will bepreferential orientation in a specific direction. Usually it is in thedirection in which the process is conducted and is called the machinedirection (MD). Many of the products are purposely oriented to provideimproved properties in a particular direction. If a product is meltprocessed, it will have some degree of preferential orientation. In caseof solvent processed materials, orientation may be induced duringprocessing by methods such as shearing the polymer solution followed byimmediate precipitation or quenching to the desired geometry in order tolock in the orientation during the shearing process. Alternately, if thepolymers have rigid rod like chemical structure then it will orientduring processing due to the liquid crystalline morphology in thepolymer solution.

The orientation state will depend on the type of deformation and thetype of polymer. Even though a material is highly deformed or drawn, itis not necessary to impart high levels of orientation as the polymerchains may relax back to their original state. This generally occurs inpolymers that are very flexible at the draw temperature. Therefore,several factors may influence the state of orientation in a givenpolymer system, including rate of deformation for example, strain rate,shear rate, frequency, and the like, amount of deformation or drawratio, temperature, molecular weight and its distribution, chainconfiguration for example, stereoregularity, geometrical isomers, andthe like, chain architecture, for example, linear, branched,cross-linked, dendritic and the like, chain stiffness, for example,flexible, rigid, semi-rigid, and the like, polymer blends, copolymertypes, for example, random, block, alternating, and the like, and thepresence of additives, for example, plasticizers, hard and soft fillers,long and short fibers, therapeutic agents and the like.

Since polymers consist of two phases; namely, crystalline and amorphous,the effect of orientation will differ for these phases, and thereforethe final orientation may not be the same for these two phases in asemi-crystalline polymer system. This is because the flexible amorphouschains will respond differently to the deformation and the loadingconditions than the hard crystalline phase.

Different phases may be formed after inducing orientation and itsbehavior depends on the chemistry of the polymer backbone. A homogenousstate such as a completely amorphous material would have a singleorientation behavior. However, in polymers that are semi-crystalline,block co-polymers or composites, for example, fiber reinforced, filledsystems and liquid crystals, the orientation behavior needs to bedescribed by more than one parameter. Orientation behavior, in general,is directly proportional to the material structure and orientationconditions. There are several common levels of structure that exist in apolymeric system, such as crystalline unit cell, lamellar thickness,domain size, spherulitic structures, oriented superstructures, phaseseparated domains in polymer blends and the like.

Processes

According to the systems and methods of the present invention, avascular closure device comprised of polymeric, bioabsorbable materialsmay be made by any of a variety of processes. The processes used toprepare the antimicrobial vascular closure device are preferably lowtemperature processes in order to minimize the degradation of the agentsthat are unstable at high temperatures and are incorporated into thematrix of bioabsorbable polymeric materials comprising the device.Processing methods may comprise forming the device from bioabsorbablepolymeric materials via low temperature, solution-based processes usingsolvents as by, for example, fiber spinning, including dry and wetspinning, electrostatic fiber spinning, co-mingled fibers, solventextraction, coating, wire-coating, hollow fiber and membrane spinning,spinning disk (thin films with uniform thickness), ink-jet printing(three dimensional printing and the like), lyophilization, extrusion andco-extrusion, supercritical fluids, solvent cast films, or solvent casttubes. Alternately, the vascular closure devices may also be prepared bymore conventional polymer processing methods in melt condition for drugsor agents that are stable at high temperature as by, for example, fiberspinning, extrusion, co-extrusion, injection molding, blow molding,pultrusion and compression molding. Alternately, the agents may also beincorporated in the device by diffusion through the polymer matrix. Thismay be achieved by several methods such as swelling the device in aagent-enriched solution followed by high-pressure diffusion or byswelling and diffusing the agent in the device using supercriticalfluids. Alternately, the drugs or agents may be sprayed, dipped, orcoated onto the device after formation thereof from the bioabsorbablepolymers. In either case, the polymer matrix, and drug or agent blendwhen provided, is then converted into a structure such as fibers, films,foams, discs/rings or tubes, for example, that is thereafter furthermanipulated into various geometries or configurations as desired.

Different processes may provide different structures, geometries orconfigurations to the bioabsorbable polymer being processed. Forexample, tubes processed from rigid polymers tend to be very stiff, butmay be very flexible when processed via electrostatic processing orlyophilization. In the former case, the tubes are solid, whereas in thelatter case, the tubes are porous. Other processes provide additionalgeometries and structures that may include fibers, microfibers, thin andthick films, discs, foams, microspheres and even more intricategeometries or configurations. The differences in structures, geometriesor configurations provided by the different processes are useful forpreparing different devices with desired dimensions, strengths, agent ordrug delivery and visualization characteristics.

In the case of a vascular closure device comprised of bioabsorbablepolymeric materials formed by supercritical fluids, such assupercritical carbon dioxide, the supercritical fluids are used to lowerprocessing temperatures during extrusion, molding or otherwiseconventional processing techniques. Different structures, such asfibers, tubes, films, or foams, may be formed using the supercriticalfluids, whereby the lower temperature processing that accompanies thesupercritical fluids tends to minimize degradation of the agents ordrugs incorporated into the structures formed.

Solvent Processing

In the case of a vascular closure device comprised of bioabsorbablepolymeric materials formed from solution, the viscosity of the polymersolution will determine the processing method used to prepare thedevices. Viscosity of the polymer solutions will, in turn, depend onfactors such as the molecular weight of the polymer, polymerconcentration, and the solvent used to prepare the solutions, processingtemperatures and shear rates.

Another method to prepare tubes or fibers from polymer solutions, forexample in the range from about 1 percent to 50 percent (wt/wt), is toextrude the solutions using an extruder with a tubular or rod die.During extrusion, the viscosity of the solution may be raised by gradualremoval or multi-stage de-volatilization of solvent from vents using,for example, vacuum pumps. Twin screw or vented screw extruders may beused for this purpose. Residual solvent may be further removed attemperatures and conditions that will not degrade the drug. The polymersolutions may also comprise antibacterial agent and other additives suchas plasticizers, other polymers and the like.

All the solvent processed devices may be prepared in different shapes,geometries and configurations. For example, the tube may be co-extrudedand/or wire coated. Other processing methodologies that are known in theart may be utilized.

Melt Processing

Vascular closure devices may also be prepared by more conventionalpolymer processing methods in melt condition for drugs or agents thatare stable at high temperature. Polymer compounding may be achieved byusing twin-screw extruders with different screw elements to achievedesired mixing and dispersion. There are also feeders to add additivesduring the compounding process to from multi-component blends orcomposites. These additives may include pellets, powders of differentsizes, short fibers or liquids. Polymer and antibacterial agent, forexample, 1 percent to about 50 percent (wt/wt) may be melt-compoundedusing a twin-screw extruder at low temperatures under low shearconditions. The compounded material may be pelletized and extruded intoa tube, fiber or other desired geometry using a single screw extruder.Other additives such as plasticizers and other polymers may also beadded to the polymer formulation during the compounding step.

In the case of a vascular device comprised of bioabsorbable materialsformed by co-extrusion, different bioabsorbable polymeric materials maybe used whereby the different polymer tubes or fibers are extrudedgenerally at the same time to form a bi-component, such as an outerlayer for tubes or sheaths in case of fibers, and a inner layer fortubes or core in case of fibers. Bioabsorbable polymeric materialshaving low melting points are extruded to form the sheath or outsidesurface, and these low melting point materials will incorporate thedrugs or other bio-active agents for eventual delivery to the patient.Materials and their blends having higher melting points are extruded toform the core or inside surface that is surrounded by the sheath. Duringprocessing, the temperatures for extruding the low melting point drugcomprising materials, for example, polycaprolactone, polydioxanone, andtheir copolymers and blends may be as low as 60 degrees C. to 100degrees C. Further, because the drugs or other bio-active agents addedto the devices made by this co-extrusion method tend to be coated ontothe device after the device has been extruded, the drugs or agents arenot exposed to the high temperatures associated with such methods.Degradation of the drugs during processing is therefore minimized.

In the case of a vascular closure device comprised of bioabsorbablepolymeric materials formed by co-mingled fibers, different bioabsorbablepolymeric materials may also be used. Contrary to the co-extrusiontechniques described above, the co-mingled fibers technique requiresthat each fiber be separately extruded and then later combined to form adevice of a desired geometry. Alternately, different fibers may also beextruded using the same spin pack but from different spinning holesthereby combining them in one step. The different bioabsorbablepolymeric materials include a first fiber having a low temperaturemelting point into which a drug is incorporated, and a second fiberhaving a higher temperature melting point.

There are several different morphological variations that may occurduring melt or solution processing bioabsorbable materials. Whensemi-crystalline polymers are processed from solution, since the solventevaporates gradually, the polymers may get sufficient time tore-crystallize before it is completely dry. It will also allow time forphase separation to occur in case of multi-component blend systems.These changes are driven by well-known theories of thermodynamics ofpolymer crystallization and phase separation. In order to prepare, forexample, amorphous tubes or films or fibers from solution, it may benecessary to remove the solvent in a relatively short time so thatkinetics will prevent crystallization and phase separation fromoccurring. For example, when the PLGA fibers are prepared from dioxanesolutions, it may be necessary to remove the solvent in a relativelyshort time, for example, a few minutes to hours at low temperatures, forexample, below 60 degrees C., after the fiber forming process to obtainan almost amorphous material. If the solvent removal process is carriedout over a long period of time, for example, 6 to 10 h, at elevatedtemperatures, for example, 60 degrees C., then PLGA may begin tocrystallize (up to 10 to 20 percent crystallinity). In case of polymerblends, it is preferred to have an amorphous system to achieve goodcompatibility between the amorphous phases of the polymers so that thephysical properties are not adversely affected. When the polymersolutions are precipitated or coagulated, the resulting structure willbe almost amorphous (1 to 5 percent crystallinity), as the solventremoval process is very fast thereby not allowing the polymer tocrystallize.

In case of melt processed materials, the tubes or films or fibers arequenched immediately after exiting the extrusion die. Therefore, thepolymers, in general, do not crystallize if the quenched temperature isbelow the glass transition temperature of the materials. In case of PGAor PLGA, the extruded fiber or tubes have very low levels ofcrystallinity (1 to 5 percent). This also makes it favorable whenpolymer blends are prepared from this process. Annealing the materialsbetween the glass transition and melt temperatures for a given period oftime will increase the amount of crystallinity. For example, PLGA fibersor tubes may be annealed at 110 degrees C. for 3 to 10 h by mountingthem over a mandrel under tension to prevent any shrinkage or buckling.The amount of crystallinity will increase from about 0 percent to about35 to 45 percent. Accordingly, this way the properties may be altered toachieve the desired morphology and physical properties.

These morphological variations in the precursor material (fibers, tubes,films, etc) will dictate to some extent the performance of the devicesprepared from these materials. Amorphous materials will absorb faster,have higher toughness values, will physically age, and may not havesufficient dimensional stability compared to crystalline material. Incontrast, crystalline material may not form compatible blends, will takea longer time to absorb, are stiffer with lower toughness values, andmay have superior physical device properties such as low creep, higherstrength, etc. For example, a material that is mechanically tested froma quenched state (higher amorphous form) and a slow cooled state (highercrystalline form) will provide a ductile high deformation behavior and abrittle behavior, respectively. This behavior is from the differences inthe crystallinity and morphological features driven by different thermaltreatments and histories. The morphological structure of a devicesurface may be modified by applying energy treatment (e.g., heat). Forexample, an amorphous surface morphology can be converted to acrystalline surface morphology by annealing it under differentconditions (temperature/time). This may result in the formation of acrystalline skin or layer on the device that may provide severalbenefits such as agent elution control and surface toughness to preventcrack formation and propagation. Therefore, it is important to balancethe structure—property—processing relationship for the materials thatare used to prepare the devices to obtain optimum performance.

The implantable medical devices of the current invention may be preparedfrom pure polymers, blends, and composites and may be used to prepareagent or drug-loaded vascular closure devices. The precursor materialmay be a fiber or a tube or a film that is prepared by any of theprocesses described above. The precursor material may be used asprepared or can be modified by quenching, annealing, orienting orrelaxing them under different conditions. Alternately, the device may beused as prepared or may be modified by quenching, annealing, orientingor relaxing them under different conditions.

Mechanical Orientation

Orientation may be imparted to fibers, tubes, films or other geometriesthat are loaded or coated with agents or drugs in the range from about 1to 50 percent. For example, drug loaded PGA tubes prepared by any of theabove-mentioned processes may be oriented at about 70 degrees C. todifferent amounts (for example, 50 percent to 300 percent) at differentdraw rates (for example, 100 mm/min to 1000 mm/min). The conditions todraw the material is important to prevent excessive fibrillation andvoid formation that may occur due to the presence of drug. If the drawtemperature is increased to a higher value (for example, 90 degrees C.),then the orientation may not be retained as the temperature oforientation is much higher than the glass transition temperature of PGA(about 45 degrees C.) and would cause relaxation of the polymer chainsupon cooling.

Other methods of orienting the materials may include multi-stage drawingprocesses in which the material or device may be drawn at different drawrates at different temperatures before or after intermediate controlledannealing and relaxation steps. This method allows increasing the totaldraw ratio for a given material that is not otherwise possible inone-step drawing due to limitations of the material to withstand highdraw ratio. These steps of orientation, annealing and relaxation willimprove the overall strength and toughness of the material.

Polymeric Materials

Polymeric materials may be broadly classified as synthetic, naturaland/or blends thereof. Within these broad classes, the materials may bedefined as biostable or biodegradable. Examples of biostable polymersinclude polyolefins, polyamides, polyesters, fluoropolymers, andacrylics. Examples of natural polymers include polysaccharides andproteins.

Bioabsorobable and/or biodegradable polymers consist of bulk and surfaceerodable materials. Surface erosion polymers are typically hydrophobicwith water labile linkages. Hydrolysis tends to occur fast on thesurface of such surface erosion polymers with no water penetration inbulk. The initial strength of such surface erosion polymers tends to below however, and often such surface erosion polymers are not readilyavailable commercially. Nevertheless, examples of surface erosionpolymers include polyanhydrides such as poly (carboxyphenoxyhexane-sebacic acid), poly (fumaric acid-sebacic acid), poly(carboxyphenoxy hexane-sebacic acid), poly (imide-sebacic acid) (50-50),poly (imide-carboxyphenoxy hexane) (33-67), and polyorthoesters(diketene acetal based polymers).

Bulk erosion polymers, on the other hand, are typically hydrophilic withwater labile linkages. Hydrolysis of bulk erosion polymers tends tooccur at more uniform rates across the polymer matrix of the device.Bulk erosion polymers exhibit superior initial strength and are readilyavailable commercially.

Examples of bulk erosion polymers include poly (α-hydroxy esters) suchas poly (lactic acid), poly (glycolic acid), poly (caprolactone), poly(p-dioxanone), poly (trimethylene carbonate), poly (oxaesters), poly(oxaamides), and their co-polymers and blends. Some commercially readilyavailable bulk erosion polymers and their commonly associated medicalapplications include poly (dioxanone) [PDS® suture available fromEthicon, Inc., Somerville, N.J.], poly (glycolide) [Dexon® suturesavailable from United States Surgical Corporation, North Haven, Conn.],poly (lactide)-PLLA [bone repair], poly (lactide/glycolide) [Vicryl®(10/90) and Panacryl® (95/5) sutures available from Ethicon, Inc.,Somerville, N.J.], poly (glycolide/caprolactone (75/25) [Monocryl®sutures available from Ethicon, Inc., Somerville, N.J.], and poly(glycolide/trimethylene carbonate) [Maxon® sutures available from UnitedStates Surgical Corporation, North Haven, Conn.].

Other bulk erosion polymers are tyrosine derived poly amino acid[examples: poly (DTH carbonates), poly (arylates), and poly(imino-carbonates)], phosphorous containing polymers [examples: poly(phosphoesters) and poly (phosphazenes)], poly (ethylene glycol) [PEG]based block co-polymers [PEG-PLA, PEG-poly (propylene glycol), PEG-poly(butylene terephthalate)], poly (α-malic acid), poly (ester amide), andpolyalkanoates [examples: poly (hydroxybutyrate (HB) and poly(hydroxyvalerate) (HV) co-polymers].

Of course, the devices may be made from combinations of surface and bulkerosion polymers in order to achieve desired physical properties and tocontrol the degradation mechanism. For example, two or more polymers maybe blended in order to achieve desired physical properties and devicedegradation rate. Alternately, the device may be made from a bulkerosion polymer that is coated with a surface erosion polymer. The drugdelivery device may be made from a bulk erosion polymer that is coatedwith a antibacterial agent containing a surface erosion polymer. Forexample, the coating may be sufficiently thick that high loads may beachieved, and the bulk erosion polymer may be made sufficiently thickthat the mechanical properties of the device are maintained even afterall of the drug has been delivered and the surface eroded.

Shape memory polymers may also be used. Shape memory polymers arecharacterized as phase segregated linear block co-polymers having a hardsegment and a soft segment. The hard segment is typically crystallinewith a defined melting point, and the soft segment is typicallyamorphous with a defined glass transition temperature. The transitiontemperature of the soft segment is substantially less than thetransition temperature of the hard segment in shape memory polymers. Ashape in the shape memory polymer is memorized in the hard and softsegments of the shape memory polymer by heating and cooling techniques.Shape memory polymers may be biostable and bioabsorbable. Bioabsorbableshape memory polymers are relatively new and comprise thermoplastic andthermoset materials. Shape memory thermoset materials may include poly(caprolactone) dimethylacrylates, and shape memory thermoplasticmaterials may include poly (caprolactone) as the soft segment and poly(glycolide) as the hard segment.

The selection of the bioabsorbable polymeric material used to comprisethe device according to the invention is determined according to manyfactors including, for example, the desired absorption times andphysical properties of the bioabsorbable materials, and the geometry ofthe drug delivery device.

The local delivery of the antibacterial agent/therapeutic agentcombinations may be utilized to treat a wide variety of conditionsutilizing any number of medical devices, or to enhance the functionand/or life of the device. For example, intraocular lenses, placed torestore vision after cataract surgery is often compromised by theformation of a secondary cataract. The latter is often a result ofcellular overgrowth on the lens surface and can be potentially minimizedby combining a drug or drugs with the device. Other medical deviceswhich often fail due to tissue in-growth or accumulation ofproteinaceous material in, on and around the device, such as shunts forhydrocephalus, dialysis grafts, colostomy bag attachment devices, eardrainage tubes, leads for pace makers and implantable defibrillators canalso benefit from the device-drug combination approach. Devices whichserve to improve the structure and function of tissue or organ may alsoshow benefits when combined with the appropriate agent or agents. Forexample, improved osteointegration of orthopedic devices to enhancestabilization of the implanted device could potentially be achieved bycombining it with agents such as bone-morphogenic protein. Similarlyother surgical devices, sutures, staples, anastomosis devices, vertebraldisks, bone pins, suture anchors, hemostatic barriers, clamps, screws,plates, clips, vascular implants, tissue adhesives and sealants, tissuescaffolds, various types of dressings, bone substitutes, intraluminaldevices, including stents, stent-grafts and other devices for repairinganeurysims, and vascular supports could also provide enhanced patientbenefit using this drug-device combination approach. Perivascular wrapsmay be particularly advantageous, alone or in combination with othermedical devices. The perivascular wraps may supply additional drugs to atreatment site. Essentially, any other type of medical device may becoated in some fashion with a drug or drug combination, which enhancestreatment over use of the singular use of the device or pharmaceuticalagent.

In addition to various medical devices, the coatings on these devicesmay be used to deliver therapeutic and pharmaceutic agents including,all the compounds described above and anti-proliferative agents,anti-throrombogenic agents, anti-restenotic agents, anti-infectiveagents, anti-viral agents, anti-bacterial agents, anti-fungal agents,anti-inflammatory agents, cytostatic agents, cytotoxic agents,immunosuppressive agents, anti-microbial agents, anti-calcificationagents, anti-encrustation agents, statins, hormones, anti-cancer agents,anti-coagulants, anti-migrating agents and tissue growth promotingagents.

As described herein, various drugs or agents may be incorporated intothe medical device by a number of mechanisms, including blending it withthe polymeric materials or affixing it to the surface of the device.Different drugs may be utilized as therapeutic agents, includingsirolimus, or rapamycin, heparin, everolimus, tacrolimus, paclitaxel,cladribine as well as classes of drugs such as statins. These drugsand/or agents may be hydrophilic, hydrophobic, lipophilic and/orlipophobic.

Rapamycin is a macroyclic triene antibiotic produced by streptomyceshygroscopicus as disclosed in U.S. Pat. No. 3,929,992. It has been foundthat rapamycin inhibits the proliferation of vascular smooth musclecells in vivo. Accordingly, rapamycin may be utilized in treatingintimal smooth muscle cell hyperplasia, restenosis and vascularocclusion in a mammal, particularly following either biologically ormechanically mediated vascular injury, or under conditions that wouldpredispose a mammal to suffering such a vascular injury. Rapamycinfunctions to inhibit smooth muscle cell proliferation and does notinterfere with the re-endothelialization of the vessel walls.

The drugs, agents or compounds described herein may be utilized incombination with any number of medical devices, and in particular, withimplantable medical devices such as stents and stent-grafts. Otherdevices such as vena cava filters and anastomosis devices may be usedwith coatings having drugs, agents or compounds therein or the devicesthemselves may be fabricated with polymeric materials that have thedrugs contained therein.

Any of the above-described medical devices may be utilized for the localdelivery of drugs, agents and/or compounds to other areas, notimmediately around the device itself. In order to avoid the potentialcomplications associated with systemic drug delivery, the medicaldevices of the present invention may be utilized to deliver the agentsto areas adjacent to the medical device. For example, a triclosan coatedvascular closure plug may deliver the agent to the tissues surroundingthe plug. The degree of tissue penetration depends on a number offactors, including the drug, agent or compound, the concentrations ofthe drug and the release rate of the agent.

The amount of agent incorporated within the device according to thesystems and methods of the present invention may range from about 0 to99 percent (percent weight of the device). The drugs or other agents maybe incorporated into the device in different ways. For example, thedrugs or other agents may be coated onto the device after the device hasbeen formed, wherein the coating is comprised of bioabsorbable polymersinto which the drugs or other agents are incorporated. Alternately, thedrugs or other agents may be incorporated into the matrix ofbioabsorbable materials comprising the device. The drugs or agentsincorporated into the matrix of bioabsorbable polymers may be in anamount the same as, or different than, the amount of drugs or agentsprovided in the coating techniques discussed earlier if desired. Thesevarious techniques of incorporating drugs or other agents into, or onto,the device may also be combined to optimize performance of the device,and to help control the release of the drugs or other agents from thedevice.

Where the drug or agent is incorporated into the matrix of bioabsorbablepolymers comprising the device, for example, the drug or agent willrelease by diffusion and during degradation of the device. The amount ofdrug or agent released by diffusion will tend to release for a longerperiod of time than occurs using coating techniques, and may often moreeffectively treat local and diffuse conditions thereof. Polymercompositions and their diffusion and absorption characteristics willcontrol agent or drug elution profile for these devices. The releasekinetics will be controlled by diffusion and polymer absorption.Initially, most of the agent or drug will be released by diffusion fromthe device surfaces and bulk and will then gradually transition torelease due to polymer absorption. There may be other factors that willalso control drug or agent release. If the polymer composition is fromthe same monomer units (e.g., lactide; glycolide), then the diffusionand absorption characteristics will be more uniform compared to polymersprepared from mixed monomers. Also, if there are layers of differentpolymers with different drug in each layer, then there will be morecontrolled release of drug from each layer. There is a possibility ofagent or drug present in the device until the polymer fully absorbs thusproviding drug release throughout the device life cycle.

The vascular closure device according to the systems and methods of thepresent invention preferably retains its integrity during the activedrug delivery phase of the device. After drug delivery is achieved, thestructure of the device ideally disappears as a result of thebioabsorption of the materials comprising the device. The bioabsorbablematerials comprising the drug delivery device are preferablybiocompatible with the tissue in which the device is implanted such thattissue interaction with the device is minimized even after the device isdeployed within the patient. Minimal inflammation of the tissue in whichthe device is deployed is likewise preferred even as degradation of thebioabsorbable materials of the device occurs. In order to providemultiple drug therapy, enriched or encapsulated drug particles orcapsules may be incorporated in the polymer matrix. Some of theseactives may provide different therapeutic benefits such asanti-inflammatory, anti-thrombotic; etc.

In accordance with another exemplary embodiment, the vascular closuredevice described herein may be utilized as antibacterial agents or drugdelivery devices wherein the agent is affixed to the surface of thedevice. Typical material properties for coatings include flexibility,ductility, tackiness, durability, adhesion and cohesion. Biostable andbioabsorbable polymers that exhibit these desired properties includemethacrylates, polyurethanes, silicones, poly (vinyl acetate), poly(vinyl alcohol), ethylene vinyl alcohol, poly (vinylidene fluoride),poly (lactic acid), poly (glycolic acid), poly (caprolactone), poly(trimethylene carbonate), poly (dioxanone), polyorthoester,polyanhydrides, polyphosphoester, polyaminoacids as well as theircopolymers and blends thereof.

In addition to the incorporation of therapeutic agents, the surfacecoatings may also include other additives such as radiopaqueconstituents, chemical stabilizers for both the coating and/or thetherapeutic agent, radioactive agents, tracing agents such asradioisotopes such as tritium (i.e. heavy water) and ferromagneticparticles, and mechanical modifiers such as ceramic microspheres as willbe described in greater detail subsequently. Alternatively, entrappedgaps may be created between the surface of the device and the coatingand/or within the coating itself. Examples of these gaps include air aswell as other gases and the absence of matter (i.e. vacuum environment).These entrapped gaps may be created utilizing any number of knowntechniques such as the injection of microencapsulated gaseous matter.

As described above, different agents may be utilized as therapeuticagents, including sirolimus, heparin, everolimus, tacrolimus,paclitaxel, cladribine as well as classes of drugs such as statins.These drugs and/or agents may be hydrophilic, hydrophobic, lipophilicand/or lipophobic. The type of agent will play a role in determining thetype of polymer. The amount of the drug in the coating may be varieddepending on a number of factors including, the storage capacity of thecoating, the drug, the concentration of the drug, the elution rate ofthe drug as well as a number of additional factors. The amount of drugmay vary from substantially zero percent to substantially one hundredpercent. Typical ranges may be from about less than one percent to aboutforty percent or higher. Drug distribution in the coating may be varied.The one or more drugs may be distributed in a single layer, multiplelayers, single layer with a diffusion barrier or any combinationthereof.

Different solvents may be used to dissolve the drug/polymer blend toprepare the coating formulations. Some of the solvents may be good orpoor solvents based on the desired drug elution profile, drug morphologyand drug stability.

There are several ways to coat the device that are disclosed in theprior art. Some of the commonly used methods include spray coating; dipcoating; electrostatic coating; fluidized bed coating; and supercriticalfluid coatings.

Some of the processes and modifications described herein that may beused will eliminate the need for polymer to hold the agent on thevascular closure device. Device surfaces may be modified to increase thesurface area in order to increase agent or drug content andtissue-device interactions. Nanotechnology may be applied to createself-assembled nanomaterials that can contain tissue specific agent/drugcontaining nanoparticles. Microstructures may be formed on surfaces bymicroetching in which these nanoparticles may be incorporated. Themicrostructures may be formed by methods such as laser micromachining,lithography, chemical vapor deposition and chemical etching.Microstructures may be added to the device surface by vapor depositiontechniques. Microstructures have also been fabricated on polymers andmetals by leveraging the evolution of micro electro-mechanical systems(MEMS) and microfluidics. Examples of nanomaterials include carbonnanotubes and nanoparticles formed by sol-gel technology. Therapeuticagents may be chemically or physically attached or deposited directly onthese surfaces. Combination of these surface modifications may allowagent or drug release at a desired rate. A top-coat of a polymer may beapplied to control the initial burst due to immediate exposure of drugin the absence of polymer coating.

As described above, vascular closure devices may contain antimicrobialor therapeutic agents as a coating, e.g. a surface modification.Alternatively, the agents may be incorporated into the device structure,e.g. a bulk modification that may not require a coating. For devicesprepared from biostable and/or bioabsorbable polymers, the coating, ifused, could be either biostable or bioabsorbable. However, as statedabove, no coating may be necessary because the device itself isfabricated from a delivery depot. This embodiment offers a number ofadvantages. For example, higher concentrations of the therapeutic agentor agents may be achievable such as about >50 percent by weight. Inaddition, with higher concentrations of therapeutic agent or agents,agent delivery is achievable for greater durations of time.

The sterilization process of the present invention is particularlyadapted to the challenges of sterilizing drug coated medical devices.Specifically, the sterilization process is designed to remove allbiological contaminants without affecting the drug, agent or compound orthe polymeric material comprising the device or the coating.

Medical devices typically are sterilized to render microorganismslocated thereon non-viable. In particular, sterile is understood in thefield of art to mean a minimum sterility assurance level of 10⁻⁶.Examples of sterilization processes are described in U.S. Pat. Nos.3,815,315, 3,068,864, 3,767,362, 5,464,580, 5,128,101 and 5,868,244,each of which; is incorporated herein in its entirety. Specifically,absorbable medical devices may be sensitive to radiation and heat.Accordingly, it may be desirable to sterilize such devices usingconventional sterilant gases or agents, such as, for example, ethyleneoxide gas. Upon completion of the sterilization process, theantimicrobial medical device, the delivery system, the package and/orthe containment compartment have thereon an amount of the antimicrobialagent effective to substantially inhibit colonization of bacteria on oradjacent the antimicrobial device, the package and/or the containmentcompartment.

In accordance with one exemplary embodiment, a low temperaturesterilization method may be utilized to sterilize the devices of thepresent invention. The method comprises the steps of positioning atleast one packaged, drug coated or drug containing medical device in asterilization chamber, creating a vacuum in the sterilization chamber,increasing and maintaining the temperature in the sterilization chamberin the range from about twenty-five degrees C. to about forty degrees C.and the relative humidity in the sterilization chamber in the range fromabout forty percent to about eighty-five percent for a firstpredetermined period, injecting a sterilization agent at a predeterminedconcentration into the sterilization chamber and maintaining thetemperature in the sterilization chamber in the range from abouttwenty-five degrees C. to about forty degrees C. and the relativehumidity in the range from about forty percent to about eighty-fivepercent for a second predetermined period, and removing thesterilization agent from the sterilization chamber through a pluralityof vacuum and nitrogen washes over a third predetermined period, thetemperature in the sterilization chamber being maintained at atemperature in the range from about thirty degrees C. to about fortydegrees C.

In accordance with another exemplary embodiment, a low temperaturesterilization method may be utilized to sterilize the devices of thepresent invention. The method comprising the steps of loading the atleast one packaged, drug coated medical device in a preconditioningchamber, the preconditioning chamber being maintained at a firstpredetermined temperature and a first predetermined relative humidityfor a first predetermined time period, positioning at least onepackaged, drug coated medical device in a sterilization chamber creatinga vacuum in the sterilization chamber increasing and maintaining thetemperature in the sterilization chamber in the range from abouttwenty-five degrees C. to about forty degrees C. and the relativehumidity in the sterilization chamber in the range from about fortypercent to about eighty-five percent for a first predetermined periodinjecting a sterilization agent at a predetermined concentration intothe sterilization chamber and maintaining the temperature in thesterilization chamber in the range from about twenty-five degrees C. toabout forty degrees C. and the relative humidity in the range from aboutforty percent to about eighty-five percent for a second predeterminedperiod, and removing the sterilization agent from the sterilizationchamber through a plurality of vacuum and nitrogen washes over a thirdpredetermined period, the temperature in the sterilization chamber beingmaintained at a temperature in the range from about thirty degrees C. toabout forty degrees C.

In each embodiment described above, the sterilization or sterilizingagent may comprise ethylene oxide or any other suitable agent. Thenitrogen washes, which serve to remove the ethylene oxide may bereplaced with other suitable gases, including any of the noble gases.

Other sterilization methods may also be used, such gamma and electronbeam radiations. In these methods the dosage should be low so that agentor drug in the devices is not adversely affected. The dosage may rangefrom about one to four mrad and more preferably below 2 mrad. Radiationsterilized polymers will absorb relatively faster than ethylene oxidesterilized polymers.

Although shown and described is what is believed to be the mostpractical and preferred embodiments, it is apparent that departures fromspecific designs and methods described and shown will suggest themselvesto those skilled in the art and may be used without departing from thespirit and scope of the invention. The present invention is notrestricted to the particular constructions described and illustrated,but should be constructed to cohere with all modifications that may fallwithin the scope for the appended claims.

What is claimed is:
 1. A method of making a vascular closure devicecomprising: forming a biocompatible polymer into at least one fiberhaving a fiber matrix by melt spinning an absorbable polymer resinmultifilament fibers with different denier and tenacity; applying a spinfinish to the surface of the multifilament fibers; crimping and cuttingthe multifilament fibers into short staple fibers; providing asnon-woven mat from the short staple fibers; rinsing the non-woven matwith solvent drying the non-woven mat; cutting the non-woven mat into adesired geometry including at least a cylindrical plug having at leastone interstitial space between at least one randomly oriented fiber inthe at least one cylindrical plug; dispersing at least one agent, intherapeutic dosage, in the fiber matrix of the at least one fiber, theagent being configured for controlled elution therefrom.
 2. The methodof claim 1 wherein incorporating the at least one agent, in therapeuticdosage, in the fiber matrix of the at least one fiber comprisesdispersing the at least one agent in the at least one fiber during oneof melt spinning step, the applying of the spin finish or the rinsingstep.
 3. The method of claim 2 wherein forming the biocompatible polymerinto at least one fiber comprises extruding the at least one fiber, theextruded fiber having a three dimensional shape with a longitudinallength.
 4. The method of claim 3 wherein incorporating at least oneagent, in therapeutic dosage, in the fiber matrix of the at least onefiber comprises adding the at least one agent to the at least one fiberwhile extruding the at least one fiber.
 5. The method of claim 4 whereinadding the at least one agent to the at least one fiber while extrudingthe at least one fiber comprises allowing uniform dispersion of theagent into the at least one fiber.
 6. The method of claim 4 whereinadding the at least one agent to the at least one fiber comprisesco-extruding bi-components of the at least one fiber and adding the atleast one agent to at least one bi-component of the at least one fiber.7. The method of claim 6 wherein co-extruding bi-components of the atleast one fiber results in the at least one fiber having a sheath and acore.
 8. The method of claim 6 wherein co-extruding bi-components of theat least one fiber results in the at least one fiber comprising at leasttwo longitudinally adjacent components.
 9. The method of claim 1 furthercomprising dispersing the at least one agent on the at least one fiberafter one of the rinsing step or the cutting step into the plugs. 10.The method of claim 9 wherein dispersing the at least one agent on theat least one fiber comprises dipping the at least one fiber in asolution comprising the at least one agent.
 11. The method of claim 1further comprising dispersing the at least one agent on the at least onefiber comprises spraying the at least one fiber with a solutioncomprising the at least one agent.
 12. The method of claim 9 whereindispersing the at least one agent on the at least one fiber comprisesdepositing the at least one agent on the at least one fiber using anelectrostatic deposition process.
 13. The method of claim 9 whereindispersing the at least one agent on the at least one fiber comprisesdepositing the at least one agent on the at least one fiber using avapor deposition process.
 14. The method of claim 1 further comprisingdispersing the at least one agent into the at least one interstitialspace in the fibrous structure.
 15. The method of claim 14 whereindispersing the at least one agent into the at least one interstitialspace comprises spraying fibrous structure with a solution comprisingthe at least one agent.
 16. The method of claim 14 wherein dispersingthe at least one agent into the at least one interstitial spacecomprises dipping the fibrous structure in a solution comprising the atleast one agent.
 17. The method of claim 14 wherein dispersing the atleast one agent into the at least one interstitial space comprisesdepositing the at least one agent in the fibrous structure using anelectrostatic deposition process.
 18. The method of claim 14 whereindispersing the at least one agent into the at least one interstitialspace comprises depositing the at least one agent in the fibrousstructure using a vapor deposition process.